Risk of recurrence after neoadjuvant chemotherapy and transoral robotic surgery in patients with oropharynx cancer that avoid adjuvant radiation

Abstract Background De‐escalation strategies for newly‐diagnosed p16‐positive oropharyngeal squamous cell carcinoma (p16+ OPSCC), aim to reduce treatment‐related morbidity without compromising disease control. One strategy is neoadjuvant cisplatin and docetaxel chemotherapy (NAC + S) before transoral robotic surgery, with pathology‐based risk‐adapted adjuvant treatment. Methods We examined the recurrence‐free survival (RFS) for patients who received NAC + S. Results Comparing outcomes in 103 patients between 2008 and 2023, 92% avoided adjuvant treatment and showed significantly higher 2‐year recurrence‐free survival (RFS) compared to those with adjuvant treatment (95.9% vs. 43.8%, p = 0.0049) Conclusion Our findings suggest that pathology‐based risk‐adapted omission of adjuvant treatment following NAC + S does not appear to elevate recurrence risk and that NAC may identify patients with favorable tumor biology, yielding a 2‐year RFS probability exceeding 95% without adjuvant treatment. Further, the study identifies a patient subset experiencing disease recurrence despite triple modality therapy. Despite limitations, including a retrospective design and modest sample size, the data advocate for controlled NAC + S studies.

Treatment de-escalation aims to reduce long-term treatment-associated morbidity while maintaining noninferior oncologic control. 2,5eoadjuvant cisplatin and docetaxel chemotherapy before transoral robotic surgery (NAC + S) for newlydiagnosed p16+ OPSCC is a de-escalation strategy that allows for complete avoidance of surgical pathology-based risk-adapted adjuvant radiation therapy in many patients. 6,7Further, 5-year disease-free survival (DFS) compared favorably to a historical cohort of similar patients undergoing primary concurrent chemoradiotherapy (CRT). 6Yet, concern over whether increased risk of recurrence exists in NAC + S patients who avoid risk-adapted adjuvant treatment when it might have been indicated without NAC.To address this concern, we performed a retrospective study to compare RFS in patients with newly-diagnosed p16+ OPSCC treated with NAC + S with or without risk-adapted adjuvant treatment.

| Study population
This study was approved by the George Washington University School of Medicine and Health Sciences Institutional Review Board (NCR234857) and informed consent exemption was granted.Age at diagnosis, sex, race and ethnicity, smoking status, clinical and pathologic TNM and overall stage (AJCC8), treatment modalities received, pathological complete response (pCR) and recurrence during the surveillance period were reviewed for patients with newly-diagnosed p16+ OPSCC treated with NAC + S ± risk-adapted adjuvant treatment 6,7 in a single institution between 2008 and 2023.

| Outcomes and statistical analysis
Recurrence Free Survival (RFS) was defined as time between date of last treatment and date of last follow-up/recurrence.The probability of RFS was estimated using the Kaplan-Meier method.A log-rank test and a hazard ratio were used to test differences between groups.Pathological complete response probabilities were calculated along with Wilson 95% confidence intervals (CIs).Survival analyses were conducted using SAS, version 9.4 software (SAS Institute Inc).

| RESULTS
One hundred and three patients were studied.Mean age was 62.4 years, 87.4% were men.

| DISCUSSION
Following curative-intent surgery for patients with newlydiagnosed p16+ OPSCC, patients with high-risk pathologic features receive adjuvant treatment that aims to reduce the risk of recurrence.Here, we observed two-year RFS probability of >95% in patients that were treated with NAC + S alone, indicating that NAC may select patients with favorable tumor biology that are at low risk of recurrence, even when adjuvant treatment is totally avoided.The observed RFS of patients treated with NAC + S alone is similar to that observed in the low-and intermediate-risk arms of the ECOG 3311 study. 2 This work also identifies a subset of patients with newly-diagnosed p16+ OPSCC that develop disease relapse despite triple modality therapy (NAC, surgery and adjuvant radiation).Additional studies are needed to understand the biologic features driving this poor prognosis.Limitations of our study include the retrospective design, short follow-up period for some patients, small sample size overall and especially for patients receiving adjuvant treatment.Despite these limitations, this data suggests that prospective, controlled NAC + S clinical studies that allow for risk-adapted determination of the need for adjuvant treatment are not placing patients at increased risk of recurrence if adjuvant treatment is avoided.(supporting); writing -original draft (supporting); writing -review and editing (equal).Charalampos S. Floudas: Conceptualization (equal); data curation (supporting); formal analysis (supporting); methodology (equal); writingoriginal draft (lead); writing -review and editing (lead).

Table 1
Demographic, clinical, and treatment characteristics.
lists patientT A B L E 1